Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.
Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.
T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e. lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.
A central event in both humoral and cell mediated immune responses is the activation and clonal expansion of helper T cells. Helper T cell activation is initiated by the interaction of the T cell receptor (TCR)—CD3 complex with an antigen-MHC on the surface of an antigen presenting cell. This interaction mediates a cascade of biochemical events that induce the resting helper T cell to enter a cell cycle (the G0 to G1 transition) and results in the expression of a high affinity receptor for IL-2 and sometimes IL-4. The activated T cell progresses through the cycle proliferating and differentiating into memory cells or effector cells.
The immune system of mammals consists of a number of unique cells that act in concert to defend the host from invading bacteria, viruses, toxins and other non-host substances. The cell type mainly responsible for the specificity of the immune system is called the lymphocyte, of which there are two types, B and T cells. T cells take their designation from being developed in the thymus, while B cells develop in the bone marrow. The T-cell population has several subsets, such as suppressor T cells, cytotoxic T cells and T helper cells. The T-helper cell subsets define 2 pathways of immunity: Th1 and Th2. The Th1 cells, a functional subset of CD4+ cells, are characterized by their ability to boost cell mediated immunity. The Th1 cell produces cytokines Il-2 and interferon-γ, and are identified by the absence of Il-10, Il-4, Il-5 and Il-6.
The Th2 cell is also a CD4+ cell, but is distinct from the Th1 cell. The Th2 cells are responsible for antibody production and produce the cytokines Il-4, Il-5, Il-10 and Il-13. (see FIG. 1). These cytokines play an important role in making the Th1 and Th2 responses mutually inhibitory. The interferon-γ that is produced by the Th1 cells inhibits the proliferation of Th2 cells (FIG. 2) while IL-10 produced by the Th2 cells represses the production of interferon-γ (FIG. 2).
Members of the four helical bundle cytokine family (Bazan, J. F., 1990, Proc Natl Acad Sci USA, 87:6934-8) have been found to play a critical role in the expansion and terminal differentiation of T helper cells from a common precursor into distinct populations of Th1 and Th2 effector cells. O'Garra, A., 1998, Immunity, 8:275-83. IL-4 influence predominantly the development of Th2 cells while IL-12 is a major factor involved in the differentiation of Th1 cells. Hsieh, C. S., et al., 1993, Science, 260:547-9; Seder, R. A., et al., 1993, Proc Natl Acad Sci USA, 90:10188-92; Le Gros, G., et al., 1990, J Exp Med, 172:921-9; Swain, S. L., et al., 1991, Immunol Rev, 123:115-44. Accordingly, mice deficient in IL-4 (Kuhn, R., et al, 1991, Science, 254:707-10), IL-4 receptor chain (Noben-Trauth, N., et al., 1997, Proc Natl Acad Sci USA, 94:10838-43), or the IL-4 specific transcription factor STAT6 (Shimoda, K., et al., 1996, Nature, 380:630-3) are defective in Th2 responses, while mice deficient in IL-12 (Magram, J., et al., 1996, Immunity, 4:471-81), IL-12 receptor (IL-12R) 1 chain (Wu, C., et al., 1997, J Immunol, 159:1658-65), or the IL-12 specific transcription factor STAT4 (Kaplan, M. H., et al., 1996, Nature, 382:174-7) have impaired Th1 responses.
Th-1 and Th-2 cell subtypes are believed to be derived from the common precursor, termed a Th-0 cell. In contrast to the mutually exclusive cytokine production of the Th-1 and Th-2 subtypes, Th-0 cells produce most or all of these cytokines. The release profiles of the different cytokines for the Th-1 and Th-2 subtypes plays an active role in the selection of effector mechanisms and cytotoxic cells. The Il-2 and γ-interferon secreted by Th-1 cells tends to activate macrophages and cytotoxic cells, while the Il-4, Il-5, Il-6 and Il-10 secreted by Th-2 cells tends to increase the production of eosinophils and mast cells as well as enhance the production of antibodies including IgE and decrease the function of cytotoxic cells. Once established, the Th-1 or Th-2 response pattern is maintained by the production of cytokines that inhibit the production of the other subset. The γ-interferon produced by Th-1 cells inhibits production of Th-2 cytokines such as Il-4 and Il-10, while the Il-10 produced by Th-2 cells inhibits the production of Th-1 cytokines such as Il-2 and γ-interferon.
The upset of the delicate balance between the cytokines produced by the Th1 and Th2 cell subsets leads to a host of disorders. For example, the overproduction of Th1 cytokines can lead to autoimmune inflammatory diseases, multiple sclerosis and inflammatory bowel disease (e.g., Crohn's disease, regional enteritis, distal ileitis, granulomatous enteritis, regional ileitis, terminal ileitis). Similarly, overproduction of Th2 cytokines leads to allergic disorders, including anaphylactic hypersensitivity, asthma, allergic rhinitis, atopic dermatitis, vernal conjunctivitis, eczema, urticaria and food allergies. Umetsu et al., Soc. Exp. Biol. Med. 215: 11-20 (1997).
WO 97/44455 filed 19 May 1997 and Sprecher et al., Biochem. Biophys. Res. Commun. 246: 82-90 (1998) describe cytokine receptor molecules possessing a certain degree of sequence identity with the murine and human TCCR molecules herein. The murine and human prior art cytokine receptors are purported to be expressed in lymphoid tissue, including the thymus, spleen, lymph nodes and peripheral blood leukocytes—and are further indicated to be present on both B- and T-cells and have a function relating to the proliferation, differentiation and/or activation of immune cells, perhaps in the development and regulation of the immune response. However, WO97/44455 and Sprecher et al., supra identify neither the precise role of TCCR and its homologs in the mediation of T-cell differentiation and cytokine release profiles into Th1 subtype and Th2 subtype, nor the host of disorders that are implicated by the release of the cytokine T-cell subtypes.